Integrated delivery device for continuous glucose sensor

ABSTRACT

Abstract of the Disclosure 
     Systems and methods for integrating a continuous glucose sensor, including a receiver, a medicament delivery device, and optionally a single point glucose monitor are provided.  Manual integrations provide for a physical association between the devices wherein a user (for example, patient or doctor) manually selects the amount, type, and/or time of delivery.  Semi-automated integration of the devices includes integrations wherein an operable connection between the integrated components aids the user (for example, patient or doctor) in selecting, inputting, calculating, or validating the amount, type, or time of medicament delivery of glucose values, for example, by transmitting data to another component and thereby reducing the amount of user input required.  Automated integration between the devices includes integrations wherein an operable connection between the integrated components provides for full control of the system without required user interaction.

Detailed Description of the Invention Field of the Invention

The present invention relates generally to systems and methodsmonitoring glucose in a host. More particularly, the present inventionrelates to an integrated medicament delivery device and continuousglucose sensor.

Background of the Invention

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non–insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which may cause anarray of physiological derangements (for example, kidney failure, skinulcers, or bleeding into the vitreous of the eye) associated with thedeterioration of small blood vessels. A hypoglycemic reaction (low bloodsugar) may be induced by an inadvertent overdose of insulin, or after anormal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a diabetic person carries a self-monitoring bloodglucose (SMBG) monitor, which typically comprises uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a diabeticwill normally only measure his or her glucose level two to four timesper day. Unfortunately, these time intervals are so far spread apartthat the diabetic will likely find out too late, sometimes incurringdangerous side effects, of a hyper- or hypo-glycemic condition. In fact,it is not only unlikely that a diabetic will take a timely SMBG value,but the diabetic will not know if their blood glucose value is going up(higher) or down (lower) based on conventional methods, inhibiting theirability to make educated insulin therapy decisions.

Home diabetes therapy requires personal discipline of the user,appropriate education from a doctor, proactive behavior undersometimes-adverse situations, patient calculations to determineappropriate therapy decisions, including types and amounts ofadministration of insulin and glucose into his or her system, and issubject to human error. Technologies are needed that ease the burdensfaced by diabetic patients, simplify the processes involved in treatingthe disease, and minimize user error which may cause unnecessarilydangerous situations in some circumstances.

Summary of the Invention

In a first embodiment, a method for treating diabetes with an integratedglucose sensor and medicament delivery device is provided, including:receiving in a receiver a data stream from a glucose sensor, includingone or more sensor data points; calculating medicament therapyresponsive to the one or more sensor data points; validating thecalculated therapy based on at least one of data input into the receiverand data obtained from an integrated single point glucose monitor; andoutputting validated information reflective of the therapyrecommendations.

In an aspect of the first embodiment, the therapy validation isconfigured to trigger a fail-safe module, if the validation fails,wherein the user must confirm a therapy decision prior to outputtingtherapy recommendations.

In an aspect of the first embodiment, the output step includesoutputting the sensor therapy recommendations to a user interface.

In an aspect of the first embodiment, the output step includesdisplaying the sensor therapy recommendations on the user interface ofat least one of a receiver and a medicament delivery device.

In an aspect of the first embodiment, the output step includestransmitting the therapy recommendations to a medicament deliverydevice.

In an aspect of the first embodiment, the output step includesdelivering the recommended therapy via an automated delivery device.

In a second embodiment, a method for treating diabetes in a host with anintegrated glucose sensor and medicament delivery device is provided,including: receiving in a receiver medicament delivery data responsiveto medicament delivery from a medicament delivery device; receiving in areceiver a data stream from a glucose sensor, including one or moresensor data points for a time period before and after the medicamentdelivery; determining a host’s metabolic response to the medicamentdelivery; receiving a subsequent data stream from the glucose sensorincluding one or more sensor data points; and calculating medicamenttherapy responsive to the host’s metabolic response to the medicamentdelivery.

In an aspect of the second embodiment, the host’s metabolic response iscalculated using a pattern recognition algorithm.

In an aspect of the second embodiment, the step of determining a host’smetabolic response to medicament delivery is repeated when the receiverreceives additional medicament delivery data.

In an aspect of the second embodiment, the host’s metabolic responseiteratively determined for a time period exceeding one week.

In a third embodiment, a method for estimating glucose levels from anintegrated glucose sensor and medicament delivery device is provided,including: receiving in a receiver a data stream from a glucose sensor,including one or more sensor data points; receiving in the receivermedicament delivery data responsive to medicament delivery from amedicament delivery device; evaluating medicament delivery data withglucose sensor data corresponding to delivery and release times of themedicament delivery data to determine individual metabolic patternsassociated with medicament delivery; and estimating glucose valuesresponsive to individual metabolic patterns associated with themedicament delivery.

In an aspect of the third embodiment, the individual’s metabolicpatterns associated with medicament delivery are calculated using apattern recognition algorithm.

In an aspect of the third embodiment, the step of determining theindividual’s metabolic patterns to medicament delivery is repeated whenthe receiver receives additional medicament delivery data.

In an aspect of the third embodiment, the individual’s metabolicpatterns are iteratively determined for a time period exceeding oneweek.

In a fourth embodiment, an integrated system for monitoring and treatingdiabetes is provided, including: a glucose sensor, wherein the glucosesensor substantially continuously measures glucose in a host for aperiod exceeding one week, and outputs a data stream, including one ormore sensor data points; a receiver operably connected to the glucosesensor, wherein the receiver is configured to receive the data stream;and a medicament delivery device, wherein the delivery device is atleast one of physically and operably connected to the receiver.

In an aspect of the fourth embodiment, the glucose sensor includes animplantable glucose sensor.

In an aspect of the fourth embodiment, the glucose sensor includes along-term subcutaneously implantable glucose sensor.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes a syringe detachably connectable to the receiver.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes one or more transdermal patches detachably connectable to thereceiver.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes an inhaler or spray delivery device detachably connectable tothe receiver.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes a pen or jet-type injector.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes a transdermal pump.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes an implantable pump.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes a manual implantable pump.

In an aspect of the fourth embodiment, the medicament delivery deviceincludes a cell transplantation device.

In an aspect of the fourth embodiment, the medicament delivery device isdetachably connected to the receiver.

In an aspect of the fourth embodiment, the medicament delivery device isoperably connected to the receiver by a wireless connection.

In an aspect of the fourth embodiment, the medicament delivery device isoperably connected by a wired connection.

In an aspect of the fourth embodiment, further including a single pointglucose monitor, wherein the single point glucose monitor is at leastone of physically and operably connected to the receiver.

In an aspect of the fourth embodiment, the glucose sensor includes anenzyme membrane system for electrochemical detection of glucose thesingle point glucose monitor includes an enzyme membrane system forelectrochemical detection of glucose.

In an aspect of the fourth embodiment, the the receiver includes amicroprocessor, and wherein the microprocessor includes programming forcalculating and outputting medicament delivery instructions

In an aspect of the fourth embodiment, the the microprocessor furtherincludes a validation module that validates the medicament deliveryinstructions prior to outputting the instructions.

In an aspect of the fourth embodiment, the the receiver is configured toreceive medicament delivery data responsive to medicament delivery for afirst time period from the medicament delivery device.

In an aspect of the fourth embodiment, the the receiver includes amicroprocessor, and wherein the microprocessor includes programming todetermine a host’s metabolic response to the medicament delivery byevaluating the sensor data points substantially corresponding todelivery and release of the medicament delivery for the first timeperiod.

In an aspect of the fourth embodiment, the microprocessor calculatesmedicament therapy for a second time period responsive to sensor dataand the host’s metabolic response to the medicament delivery.

In an aspect of the fourth embodiment, the microprocessor includesprogramming to estimate glucose values responsive to glucose sensor dataand host’s metabolic response.

Brief Description of the Drawings

Fig. 1 is a block diagram of an integrated system of the preferredembodiments, including a continuous glucose sensor, a receiver forprocessing and displaying sensor data, a medicament delivery device, andan optional single point glucose-monitoring device.

Fig. 2 is a perspective view of a continuous glucose sensor in oneembodiment.

Fig. 3 is a block diagram of the electronics associated with acontinuous glucose sensor in one embodiment.

Figs. 4A and 4B are perspective views of an integrated system 10 in oneembodiment, wherein a receiver is integrated with a medicament deliverydevice in the form of a manual syringe, and optionally includes a singlepoint glucose monitor.

Figs. 5A to 5C are perspective views of an integrated system in oneembodiment, wherein a receiver is integrated with a medicament deliverydevice in the form of one or more transdermal patches housed within aholder, and optionally includes a single point glucose monitor.

Figs. 6A and 6B are perspective views of an integrated system in oneembodiment, wherein a receiver is integrated with a medicament deliverydevice in the form of a pen or jet-type injector, and optionallyincludes a single point glucose monitor.

Figs. 7A to 7C are perspective views of an integrated system in oneembodiment, wherein a sensor and delivery pump, which are implanted ortransdermally inserted into the patient, are operably connected to anintegrated receiver, and optionally include a single point glucosemonitor.

Fig. 8 is a block diagram that illustrates integrated system electronicsin one embodiment.

Fig. 9 is a flow chart that illustrates the process of validatingtherapy instructions prior to medicament delivery in one embodiment.

Fig. 10 is a flow chart that illustrates the process of providingadaptive metabolic control using an integrated sensor and medicamentdelivery device in one embodiment.

Fig. 11 is a flow chart that illustrates the process of glucose signalestimation using the integrated sensor and medicament delivery device inone embodiment.

Detailed Description of the Preferred Embodiment

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

Definitions

In order to facilitate an understanding of the disclosed invention, anumber of terms are defined below.

The term “continuous glucose sensor,” as used herein, is a broad termand are used in its ordinary sense, including, but not limited to, adevice that continuously or continually measures glucose concentration,for example, at time intervals ranging from fractions of a second up to,for example, 1, 2, or 5 minutes, or longer. It should be understood thatcontinual or continuous glucose sensors can continually measure glucoseconcentration without requiring user initiation and/or interaction foreach measurement, such as described with reference to U.S. Patent6,001,067, for example.

The phrase “continuous glucose sensing,” as used herein, is a broad termand is used in its ordinary sense, including, but not limited to, theperiod in which monitoring of plasma glucose concentration iscontinuously or continually performed, for example, at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes, or longer.

The term “biological sample,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, sample of ahost body, for example, blood, interstitial fluid, spinal fluid, saliva,urine, tears, sweat, or the like.

The term “host,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, mammals such as humans.

The term “biointerface membrane,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, a permeableor semi-permeable membrane that can include two or more domains and istypically constructed of materials of a few microns thickness or more,which can be placed over the sensing region to keep host cells (forexample, macrophages) from gaining proximity to, and thereby damagingthe sensing membrane or forming a barrier cell layer and interferingwith the transport of glucose across the tissue-device interface.

The term “sensing membrane,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, a permeable orsemi-permeable membrane that can be comprised of two or more domains andis typically constructed of materials of a few microns thickness ormore, which are permeable to oxygen and are optionally permeable toglucose. In one example, the sensing membrane comprises an immobilizedglucose oxidase enzyme, which enables an electrochemical reaction tooccur to measure a concentration of glucose.

The term "domain," as used herein is a broad term and is used in itsordinary sense, including, without limitation, regions of a membranethat can be layers, uniform or non-uniform gradients (for example,anisotropic), functional aspects of a material, or provided as portionsof the membrane.

As used herein, the term "copolymer," as used herein, is a broad termand is used in its ordinary sense, including, without limitation,polymers having two or more different repeat units and includescopolymers, terpolymers, tetrapolymers, etc.

The term “sensing region,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, the region of amonitoring device responsible for the detection of a particular glucose.In one embodiment, the sensing region generally comprises anon-conductive body, a working electrode (anode), a reference electrodeand a counter electrode (cathode) passing through and secured within thebody forming an electrochemically reactive surface at one location onthe body and an electronic connection at another location on the body,and a sensing membrane affixed to the body and covering theelectrochemically reactive surface. The counter electrode typically hasa greater electrochemically reactive surface area than the workingelectrode. During general operation of the sensor a biological sample(for example, blood or interstitial fluid) or a portion thereof contacts(for example, directly or after passage through one or more domains ofthe sensing membrane) an enzyme (for example, glucose oxidase); thereaction of the biological sample (or portion thereof) results in theformation of reaction products that allow a determination of the glucoselevel in the biological sample.

The term “electrochemically reactive surface,” as used herein, is abroad term and is used in its ordinary sense, including, withoutlimitation, the surface of an electrode where an electrochemicalreaction takes place. In the case of the working electrode, the hydrogenperoxide produced by the enzyme catalyzed reaction of the glucose beingdetected reacts creating a measurable electronic current (for example,detection of glucose utilizing glucose oxidase produces H₂O₂ as a byproduct, H₂O₂ reacts with the surface of the working electrode producingtwo protons (2H⁺), two electrons (2e⁻) and one molecule of oxygen (O₂)which produces the electronic current being detected). In the case ofthe counter electrode, a reducible species (for example, O₂) is reducedat the electrode surface in order to balance the current being generatedby the working electrode.

The term “electrochemical cell,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, a device inwhich chemical energy is converted to electrical energy. Such a celltypically consists of two or more electrodes held apart from each otherand in contact with an electrolyte solution. Connection of theelectrodes to a source of direct electric current renders one of themnegatively charged and the other positively charged. Positive ions inthe electrolyte migrate to the negative electrode (cathode) and therecombine with one or more electrons, losing part or all of their chargeand becoming new ions having lower charge or neutral atoms or molecules;at the same time, negative ions migrate to the positive electrode(anode) and transfer one or more electrons to it, also becoming new ionsor neutral particles. The overall effect of the two processes is thetransfer of electrons from the negative ions to the positive ions, achemical reaction.

The term “proximal” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, near to a point ofreference such as an origin or a point of attachment. For example, insome embodiments of a sensing membrane that covers an electrochemicallyreactive surface, the electrolyte domain is located more proximal to theelectrochemically reactive surface than the interference domain.

The term “distal” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, spaced relatively farfrom a point of reference, such as an origin or a point of attachment.For example, in some embodiments of a sensing membrane that covers anelectrochemically reactive surface, a resistance domain is located moredistal to the electrochemically reactive surfaces than the enzymedomain.

The term “substantially” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, being largely but notnecessarily wholly that which is specified.

The term “microprocessor,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, a computer systemor processor designed to perform arithmetic and logic operations usinglogic circuitry that responds to and processes the basic instructionsthat drive a computer.

The term “ROM,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, read-only memory, whichis a type of data storage device manufactured with fixed contents. ROMis broad enough to include EEPROM, for example, which is electricallyerasable programmable read-only memory (ROM).

The term “RAM,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, a data storage device forwhich the order of access to different locations does not affect thespeed of access. RAM is broad enough to include SRAM, for example, whichis static random access memory that retains data bits in its memory aslong as power is being supplied.

The term “A/D Converter,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, hardware and/orsoftware that converts analog electrical signals into correspondingdigital signals.

The term “RF transceiver,” as used herein, is a broad term and is usedin its ordinary sense, including, but not limited to, a radio frequencytransmitter and/or receiver for transmitting and/or receiving signals.

The terms “raw data stream” and “data stream,” as used herein, are broadterms and are used in their ordinary sense, including, but not limitedto, an analog or digital signal directly related to the analyteconcentration measured by the analyte sensor. In one example, the rawdata stream is digital data in “counts” converted by an A/D converterfrom an analog signal (for example, voltage or amps) representative ofan analyte concentration. The terms broadly encompass a plurality oftime spaced data points from a substantially continuous analyte sensor,which comprises individual measurements taken at time intervals rangingfrom fractions of a second up to, for example, 1, 2, or 5 minutes orlonger.

The term “counts,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, a unit of measurement ofa digital signal. In one example, a raw data stream measured in countsis directly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from a workingelectrode.

The term “electronic circuitry,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, thecomponents (for example, hardware and/or software) of a deviceconfigured to process data. In the case of an analyte sensor, the dataincludes biological information obtained by a sensor regarding theconcentration of the analyte in a biological fluid. U.S. Patent Nos.4,757,022, 5,497,772 and 4,787,398, which are hereby incorporated byreference in their entirety, describe suitable electronic circuits thatcan be utilized with devices of certain embodiments.

The term “potentiostat,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, an electrical systemthat controls the potential between the working and reference electrodesof a three-electrode cell at a preset value. The potentiostat forceswhatever current is necessary to flow between the working and counterelectrodes to keep the desired potential, as long as the needed cellvoltage and current do not exceed the compliance limits of thepotentiostat.

The terms “operably connected” and “operably linked,” as used herein,are broad terms and are used in their ordinary sense, including, but notlimited to, one or more components being linked to another component(s)in a manner that allows transmission of signals between the components.For example, one or more electrodes can be used to detect the amount ofglucose in a sample and convert that information into a signal; thesignal can then be transmitted to an electronic circuit. In this case,the electrode is “operably linked” to the electronic circuit. Theseterms are broad enough to include wired and wireless connectivity.

The term “algorithmically smoothed,” as used herein, is a broad term andis used in its ordinary sense, including, but not limited to,modification of a set of data to make it smoother and more continuousand remove or diminish outlying points, for example, by performing amoving average of the raw data stream.

The term “algorithm,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, the computationalprocesses (for example, programs) involved in transforming informationfrom one state to another, for example using computer processing.

The term “regression,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, finding a line inwhich a set of data has a minimal measurement (for example, deviation)from that line. Regression can be linear, non-linear, first order,second order, and so forth. One example of regression is least squaresregression.

The terms “recursive filter” and “auto-regressive algorithm,” as usedherein, are broad terms and are used in their ordinary sense, including,but not limited to, an equation in which previous averages are part ofthe next filtered output. More particularly, the generation of a seriesof observations whereby the value of each observation is partlydependent on the values of those that have immediately preceded it. Oneexample is a regression structure in which lagged response values assumethe role of the independent variables.

The terms “velocity” and “rate of change,” as used herein, are broadterms and are used in their ordinary sense, including, but not limitedto, time rate of change; the amount of change divided by the timerequired for the change. In one embodiment, these terms refer to therate of increase or decrease in an analyte for a certain time period.

The term “acceleration” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, the rate of change ofvelocity with respect to time. This term is broad enough to includedeceleration.

The term “clinical risk,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, an identified dangeror potential risk to the health of a patient based on a measured orestimated analyte concentration, its rate of change, and/or itsacceleration.

The term “clinically acceptable,” as used herein, is a broad term and isused in its ordinary sense, including, but not limited to, an analyteconcentration, rate of change, and/or acceleration associated with thatmeasured analyte that is considered to be safe for a patient.

The term “time period,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, an amount of timeincluding a single point in time and a path (for example, range of time)that extends from a first point in time to a second point in time.

The term “measured analyte values,” as used herein, is a broad term andis used in its ordinary sense, including, but not limited to, an analytevalue or set of analyte values for a time period for which analyte datahas been measured by an analyte sensor. The term is broad enough toinclude data from the analyte sensor before or after data processing inthe sensor and/or receiver (for example, data smoothing, calibration, orthe like).

The term “alarm,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, audible, visual, ortactile signal that are triggered in response to detection of clinicalrisk to a patient. In one embodiment, hyperglycemic and hypoglycemicalarms are triggered when present or future clinical danger is assessedbased on continuous analyte data.

The term “computer,” as used herein, is broad term and is used in itsordinary sense, including, but not limited to, machine that can beprogrammed to manipulate data.

The term “modem,” as used herein, is a broad term and is used in itsordinary sense, including, but not limited to, an electronic device forconverting between serial data from a computer and an audio signalsuitable for transmission over a telecommunications connection toanother modem.

Overview

Fig. 1 is a block diagram of an integrated system 10 of the preferredembodiments, including a continuous glucose sensor 12, a receiver 14 forprocessing and displaying sensor data, a medicament delivery device 16,and optionally a single point glucose-monitoring device 18. Theintegrated diabetes management system 10 of the preferred embodimentsprovides improved convenience and accuracy thus affording a diabeticpatient 8 with improved convenience, functionality, and safety in thecare of their disease.

Fig. 1 shows a continuous glucose sensor 12 that measures aconcentration of glucose or a substance indicative of the concentrationor presence of the glucose. In some embodiments, the glucose sensor 12is an invasive, minimally invasive, or non-invasive device, for examplea subcutaneous, transdermal, or intravascular device. In someembodiments, the sensor 12 may analyze a plurality of intermittentbiological samples. The glucose sensor may use any method ofglucose-measurement, including enzymatic, chemical, physical,electrochemical, spectrophotometric, polarimetric, calorimetric,radiometric, or the like. In alternative embodiments, the sensor 12 maybe any sensor capable of determining the level of an analyte in thebody, for example oxygen, lactase, insulin, hormones, cholesterol,medicaments, viruses, or the like. The glucose sensor 12 uses any knownmethod to provide an output signal indicative of the concentration ofthe glucose. The output signal is typically a raw data stream that isused to provide a useful value of the measured glucose concentration toa patient or doctor, for example.

Accordingly, a receiver 14 is provided that receives and processes theraw data stream, including calibrating, validating, and displayingmeaningful glucose values to a patient, such as described in more detailbelow. A medicament delivery device 16 is further provided as a part ofthe integrated system 10. In some embodiments, the medicament deliverydevice 16 is a manual delivery device, for example a syringe, inhaler,or transdermal patch, which is manually integrated with the receiver 14.In some embodiments, the medicament delivery device 16 is asemi-automated delivery device, for example a pen or jet-type injector,an inhaler, a spray, or pump, which provides a semi-automatedintegration with the receiver 14. In some embodiments, the medicamentdelivery device 16 is an automated delivery device, for example atranscutaneous or implantable pump system, which provides an automatedintegration with the receiver 14. In some embodiments, an optionalsingle point glucose monitor 18 is further provided as a part of theintegrated system 10, for example a self-monitoring blood glucose meter(SMBG), non-invasive glucose meter, or the like.

Conventionally, each of these devices separately provides valuableinformation and or services to diabetic patients. Thus, a typicaldiabetic patient has numerous individual devices, which they track andconsider separately. In some cases, the amount of information providedby these individual devices may require complex understanding of thenuances and implications of each device, for example types and amountsof insulin to deliver. Typically, each individual device is a silo ofinformation that functions as well as the data provided therein,therefore when the devices are able to communicate with each other,enhanced functionality and safety may be realized. For example, when acontinuous glucose monitor functions alone (for example, without dataother than that which was gathered by the device), sudden changes inglucose level are tracked, but may not be fully understood, predicted,preempted, or otherwise considered in the processing of the sensor data;however, if the continuous glucose sensor were provided with informationabout time, amount, and type of insulin injections, calories consumed,time or day, meal time, or like, more meaningful, accurate and usefulglucose estimation, prediction, and other such processing can beprovided, such as described in more detail herein. By integrating thesedevices, the information from each component can be leveraged toincrease the intelligence, benefit provided, convenience, safety, andfunctionality of the continuous glucose sensor and other integratedcomponents. Therefore, it would be advantageous to provide a device thataids the diabetic patient in integrating these individual devices in thetreatment of his/her disease.

Glucose Sensor

Fig. 2 is a perspective view of one embodiment of a continuous glucosesensor 12. In this embodiment, a body 20 and a sensing region 22 housethe electrodes and sensor electronics (Fig. 3). The three electrodeswithin the sensing region are operably connected to the sensorelectronics (Fig. 3) and are covered by a sensing membrane and abiointerface membrane (not shown), which are described in more detailbelow.

The body 20 is preferably formed from epoxy molded around the sensorelectronics, however the body may be formed from a variety of materials,including metals, ceramics, plastics, or composites thereof. Co-pendingU.S. Patent Application 10/646,333, entitled, “Optimized Sensor Geometryfor an Implantable Glucose Sensor” discloses suitable configurationssuitable for the body 20, and is incorporated by reference in itsentirety.

In one embodiment, the sensing region 22 comprises three electrodesincluding a platinum working electrode, a platinum counter electrode,and a silver/silver chloride reference electrode, for example. However avariety of electrode materials and configurations may be used with theimplantable glucose sensor of the preferred embodiments. The top ends ofthe electrodes are in contact with an electrolyte phase (not shown),which is a free-flowing fluid phase disposed between the sensingmembrane and the electrodes. In one embodiment, the counter electrode isprovided to balance the current generated by the species being measuredat the working electrode. In the case of a glucose oxidase based glucosesensor, the species being measured at the working electrode is H₂O₂.Glucose oxidase catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate according to the following reaction:Glucose + O₂− > Gluconate + H₂O₂

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂. Oxidation of H₂O₂ by the working electrodeis balanced by reduction of ambient oxygen, enzyme generated H₂O₂, orother reducible species at the counter electrode. The H₂O₂ produced fromthe glucose oxidase reaction further reacts at the surface of workingelectrode and produces two protons (2H⁺), two electrons (2e⁻), and oneoxygen molecule (O₂).

In one embodiment, a potentiostat (Fig. 3) is employed to monitor theelectrochemical reaction at the electroactive surface(s). Thepotentiostat applies a constant potential to the working and referenceelectrodes to determine a current value. The current that is produced atthe working electrode (and flows through the circuitry to the counterelectrode) is substantially proportional to the amount of H₂O₂ thatdiffuses to the working electrode. Accordingly, a raw signal can beproduced that is representative of the concentration of glucose in theuser’s body, and therefore can be utilized to estimate a meaningfulglucose value.

In some embodiments, the sensing membrane includes an enzyme, forexample, glucose oxidase, and covers the electrolyte phase. In oneembodiment, the sensing membrane generally includes a resistance domainmost distal from the electrochemically reactive surfaces, an enzymedomain less distal from the electrochemically reactive surfaces than theresistance domain, and an electrolyte domain adjacent to theelectrochemically reactive surfaces. However, it is understood that asensing membrane modified for other devices, for example, by includingfewer or additional domains, is within the scope of the preferredembodiments. Co-pending U.S. Patent Appl. No. 09/916,711, entitled,“SENSOR HEAD FOR USE WITH IMPLANTABLE DEVICES,“ which is incorporatedherein by reference in its entirety, describes membranes that can beused in some embodiments of the sensing membrane. It is noted that insome embodiments, the sensing membrane may additionally include aninterference domain that blocks some interfering species; such asdescribed in the above-cited co-pending patent application. Co-pendingU.S. Patent Application 10/695,636, entitled, “SILICONE COMPOSITION FORBIOCOMPATIBLE MEMBRANE” also describes membranes that may be used forthe sensing membrane of the preferred embodiments, and is incorporatedherein by reference in its entirety.

Preferably, the biointerface membrane supports tissue ingrowth, servesto interfere with the formation of a barrier cell layer, and protectsthe sensitive regions of the device from host inflammatory response. Inone embodiment, the biointerface membrane generally includes a celldisruptive domain most distal from the electrochemically reactivesurfaces and a cell impermeable domain less distal from theelectrochemically reactive surfaces than the cell disruptive domain. Thecell disruptive domain is preferably designed to support tissueingrowth, disrupt contractile forces typically found in a foreign bodyresponse, encourage vascularity within the membrane, and disrupt theformation of a barrier cell layer. The cell impermeable domain ispreferably resistant to cellular attachment, impermeable to cells, andcomposed of a biostable material. Copending U.S. Patent Application09/916,386, entitled, “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES,” U.S.Patent Application 10/647,065, entitled, “POROUS MEMBRANES FOR USE WITHIMPLANTABLE DEVICES,” and U.S. Provisional Patent Application60/544,722, filed February 12, 2004 entitled, “BIOINTERFACE WITHINTEGRATED MACRO- AND MICRO-ARCHITECTURE,” describe biointerfacemembranes that may be used in conjunction with the preferredembodiments, and are incorporated herein by reference in their entirety.It is noted that the preferred embodiments may be used with a short term(for example, 1 to 7 day sensor), in which case a biointerface membranemay not be required. It is noted that the biointerface membranesdescribed herein provide a continuous glucose sensor that has a useablelife of greater than about one week, greater than about one month,greater than about three months, or greater than about one year, hereinafter referred to as “long-term.”

In some embodiments, the domains of the biointerface and sensingmembranes are formed from materials such as silicone,polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF),polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA),polyether ether ketone (PEEK), polyurethanes, cellulosic polymers,polysulfones and block copolymers thereof including, for example,di-block, tri-block, alternating, random and graft copolymers.

Fig. 3 is a block diagram that illustrates the electronics associatedwith a continuous glucose sensor 12 in one embodiment. In thisembodiment, a potentiostat 24 is shown, which is operably connected toelectrodes (Fig. 2) to obtain a current value, and includes a resistor(not shown) that translates the current into voltage. An A/D converter26 digitizes the analog signal into “counts” for processing.Accordingly, the resulting raw data stream in counts is directly relatedto the current measured by the potentiostat 24.

A microprocessor 28 is the central control unit that houses ROM 30 andRAM 32, and controls the processing of the sensor electronics. It isnoted that certain alternative embodiments can utilize a computer systemother than a microprocessor to process data as described herein. In somealternative embodiments, an application-specific integrated circuit(ASIC) can be used for some or all the sensor’s central processing as isappreciated by one skilled in the art. The ROM 30 providessemi-permanent storage of data, for example, storing data such as sensoridentifier (ID) and programming to process data streams (for example,programming for data smoothing and/or replacement of signal artifactssuch as described in copending U.S. Patent Application entitled,“SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSORDATA STREAM,” filed August 22, 2003). The RAM 32 can be used for thesystem’s cache memory, for example for temporarily storing recent sensordata. In some alternative embodiments, memory storage componentscomparable to ROM 30 and RAM 32 may be used instead of or in addition tothe preferred hardware, such as dynamic RAM, static-RAM, non-static RAM,EEPROM, rewritable ROMs, flash memory, or the like.

A battery 34 is operably connected to the microprocessor 28 and providesthe necessary power for the sensor 12. In one embodiment, the battery isa Lithium Manganese Dioxide battery, however any appropriately sized andpowered battery can be used (for example, AAA, Nickel-cadmium,Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride, Lithium-ion,Zinc-air, Zinc-mercury oxide, Silver-zinc, and/or hermetically-sealed).In some embodiments the battery is rechargeable. In some embodiments, aplurality of batteries can be used to power the system. In yet otherembodiments, the receiver can be transcutaneously powered via aninductive coupling, for example. A Quartz Crystal 36 is operablyconnected to the microprocessor 28 and maintains system time for thecomputer system as a whole.

An RF Transceiver 38 is operably connected to the microprocessor 28 andtransmits the sensor data from the sensor 12 to a receiver within awireless transmission 40 via antenna 42. Although an RF transceiver isshown here, some other embodiments can include a wired rather thanwireless connection to the receiver. A second quartz crystal 44 providesthe system time for synchronizing the data transmissions from the RFtransceiver. It is noted that the transceiver 38 can be substituted witha transmitter in other embodiments. In some alternative embodimentsother mechanisms such as optical, infrared radiation (IR), ultrasonic,or the like may be used to transmit and/or receive data.

In one alternative embodiment, the continuous glucose sensor comprises atranscutaneous sensor such as described in U.S. Patent 6,565,509 to Sayet al. In another alternative embodiment, the continuous glucose sensorcomprises a subcutaneous sensor such as described with reference to U.S.Patent 6,579,690 to Bonnecaze et al. and U.S. Patent 6,484,046 to Say etal. In another alternative embodiment, the continuous glucose sensorcomprises a refillable subcutaneous sensor such as described withreference to U.S. Patent 6,512,939 to Colvin et al. In anotheralternative embodiment, the continuous glucose sensor comprises anintravascular sensor such as described with reference to U.S. Patent6,477,395 to Schulman et al. In another alternative embodiment, thecontinuous glucose sensor comprises an intravascular sensor such asdescribed with reference to U.S. Patent 6,424,847 to Mastrototaro et al.All of the above patents are incorporated in their entirety herein byreference. In general, it should be understood that the disclosedembodiments are applicable to a variety of continuous glucose sensorconfigurations.

Receiver

The preferred embodiments provide an integrated system, which includes areceiver 14 that receives and processes the raw data stream from thecontinuous glucose sensor 12. The receiver may perform all or some ofthe following operations: a calibration, converting sensor data,updating the calibration, evaluating received reference and sensor data,evaluating the calibration for the analyte sensor, validating receivedreference and sensor data, displaying a meaningful glucose value to auser, calculating therapy recommendations, validating recommendedtherapy, adaptive programming for learning individual metabolicpatterns, and prediction of glucose values, for example. Somecomplementary systems and methods associated with the receiver aredescribed in more detail with reference to co-pending U.S. PatentApplication 10/633,367, entitled, “SYSTEM AND METHODS FOR PROCESSINGANALYTE SENSOR DATA,” which is incorporated herein by reference in itsentirety. Figs. 9 to 11 describe some processes that may be programmedinto the receiver. Additionally, the receiver 14 of the preferredembodiments works together with the other components of the system (forexample, the medicament delivery device 16 and the single point glucosemonitor 18) to provide enhanced functionality, convenience, and safety,such as described in more detail herein. Figs. 4 to 7 are illustrates ofa few exemplary integrated systems of the preferred embodiments, each ofwhich include the receiver, such as described in more detail herein.

In some embodiments, the receiver 14 is a PDA- or pager-sized housing46, for example, and comprises a user interface 48 that has a pluralityof buttons 50 and a liquid crystal display (LCD) screen, which mayinclude a backlight. In some embodiments, the receiver may take otherforms, for example a computer, server, or other such device capable ofreceiving and processing the data such as described herein. In someembodiments the user interface may also include a keyboard, a speaker,and a vibrator such as described with reference to Fig. 8. The receiver46 comprises systems (for example, electronics) necessary to receive,process, and display sensor data from the glucose sensor 12, such asdescribed in more detail with reference to Fig. 8. The receiver 14processes data from the continuous glucose sensor 12 and additionallyprocesses data associated with at least one of the medicament deliverydevice 16, single point glucose meter 16, and user 8.

In some embodiments, the receiver 14 is integrally formed with at leastone of the medicament delivery device 16, and single point glucosemonitor 18. In some embodiments, the receiver 14, medicament deliverydevice 16 and/or single point glucose monitor 18 are detachablyconnected, so that one or more of the components can be individuallydetached and attached at the user’s convenience. In some embodiments,the receiver 14, medicament delivery device 16, and/or single pointglucose monitor 18 are separate from, detachably connectable to, orintegral with each other; and one or more of the components are operablyconnected through a wired or wireless connection, allowing data transferand thus integration between the components. In some embodiments, one ormore of the components are operably linked as described above, whileanother one or more components (for example, the syringe or patch) areprovided as a physical part of the system for convenience to the userand as a reminder to enter data for manual integration of the componentwith the system. Some exemplary embodiments are described with referenceto Figs. 4 to 7, however suffice it to say that each of the componentsof the integrated system may be manually, semi-automatically, orautomatically integrated with each other, and each component may be inphysical and/or data communication with another component, which mayinclude wireless connection, wired connection (for example, via cablesor electrical contacts), or the like.

Medicament Delivery Device

The preferred embodiments provide an integrated system 10, whichincludes a medicament delivery device 16 for administering a medicamentto the patient 8. The integrated medicament delivery device can bedesigned for bolus injection, continuous injection, inhalation,transdermal absorption, other method for administering medicament, orany combinations thereof. The term medicament includes any substanceused in therapy for a patient using the system 10, for example, insulin,glucacon, or derivatives thereof. Published International Application WO02/43566 describes glucose, glucagon, and vitamins A, C, or D that maybe used with the preferred embodiments. U.S. Patents 6,051,551 and6,024,090 describe types of insulin suitable for inhalation that may beused with the preferred embodiments. Patents U.S. 5,234,906, U.S.6,319,893, and EP 760677 describe various derivatives of glucagon thatmay be used with the preferred embodiments. U.S. Patent 6,653,332describes a combination therapy that may be used with the preferredembodiments. U.S. Patent 6,471,689 and WO 81/01794 describe insulinuseful for delivery pumps that may be used with the preferredembodiments. U.S. Patent 5,226,895 describes a method of providing morethan one type of insulin that may be used with the preferredembodiments. All of the above references are incorporated herein byreference in their entirety and may be useful as the medicament(s) inthe preferred embodiments.

Manual Integration

In some embodiments, the medicament delivery device 16 is a manualdelivery device, for example a syringe, inhaler, transdermal patch, celltransplantation device, and/or manual pump for manual integration withthe receiver. Manual integration includes medicament delivery deviceswherein a user (for example, patient or doctor) manually selects theamount, type, and/or time of delivery. In some embodiments, themedicament delivery device 16 is any syringe suitable for injecting amedicament, as is appreciated by one skilled in the art. One example ofa syringe suitable for the medicament delivery device of the preferredembodiments is described in U.S. Patent 5,137,511, which is incorporatedherein by reference in its entirety.

Figs. 4A and 4B are perspective views of a integrated system 10 in oneembodiment, wherein a receiver 14 is integrated with a medicamentdelivery device 16 in the form of a manual syringe 54, and optionallyincludes a single point glucose monitor 18, which will be described inmore detail elsewhere herein. The receiver 14 receives, processes, anddisplays data from the continuous glucose monitor 12, such as describedin more detail above, and may also receive, process, and display datamanually entered by the user. In some embodiments, the receiver includesalgorithms that use parameters provided by the continuous glucosesensor, such as glucose concentration, rate-of-change of the glucoseconcentration, and acceleration of the glucose concentration to moreparticularly determine the type, amount, and time of medicamentadministration. The medicament delivery device 16 is in the form of asyringe 54, which may comprise any known syringe configuration, such asdescribed in more detail above. In some embodiments, the syringe 54includes a housing, which is designed to hold a syringe as well as aplurality of types and amounts of medicament, for example fast-actinginsulin, slow-acting insulin, and glucagon. In some embodiments, thesyringe is detachably connectable to the receiver 14, and the receiver14 provides and receives information to and from the patient associatedwith the time, type, and amount of medicament administered. In someembodiments, the syringe is stored in a holder that is integral with ordetachably connected to the receiver 14. In some embodiments, thesyringe 54 may be detachable connected directly to the receiver,provided in a kit with the receiver, or other configuration, whichprovides easy association between the syringe and the receiver.

Referring now to the integration between the syringe and the receiver,it is noted that the receiver can be programmed with information aboutthe time, amount, and types of medicament that may be administered withthe syringe, for example. In some embodiments during set-up of thesystem, the patient and/or doctor manually enters information about theamounts and types of medicament available via the syringe of theintegrated system. In some alternative embodiments,manufacturer-provided data can be downloaded to the receiver so that thepatient and/or doctor can select appropriate information from menus onthe screen, for example, to provide easy and accurate data entry. Thus,by knowing the available medicaments, the receiver may be programmed tocustomize the patient’s therapy recommendations considering availabletypes and amounts of medicaments in combination with concentration,rate-of-change, and/or acceleration of the patient’s glucose. While notwishing to be bound by theory, it is believed that by storing availablemedicament therapies, the receiver is able to customize medicamentcalculations and recommend appropriate therapy based glucose on trendinformation and the preferred types and the amounts of medicamentavailable to the patient.

Subsequently in some embodiments, once the patient has administered amedicament (including via the syringe and or by other means), theamount, type, and/or time of medicament administration are input intothe receiver by the patient. Similarly, the receiver may be programmedwith standard medicaments and dosages for easy selection by the patient(for example, menus on the user interface). This information can be usedby the receiver to increase the intelligence of the algorithms used indetermining the glucose trends and patterns that may be useful inpredicting and analyzing present, past, and future glucose trends, andin providing therapy recommendations, which will be described in moredetail below. Additionally, by continuously monitoring the glucoseconcentration over time, the receiver provides valuable informationabout how a patient responds to a particular medicament, whichinformation may be used by a doctor, patient, or by the algorithmswithin the receiver, to determine patterns and provide more personalizedtherapy recommendations. In other words, in some embodiments, thereceiver includes programming that learns the patterns (for example, anindividual’s metabolic response to certain medicament deliveries andpatient behavior) and to determine an optimum time, amount, and type ofmedicament to delivery in a variety of conditions (e.g., glucoseconcentration, rate-of-change, and acceleration). While not wishing tobe bound by theory, it is believed that by continuously monitoring anindividual’s response to various medicaments, the patient’s glucoselevels can be more proactively treated, keeping the diabetic patientwithin safe glucose ranges substantially all the time.

In some embodiments, the receiver includes programming to predictglucose trends, such as described in co-pending U.S. provisional patentapplication 60/528382, entitled, “SIGNAL PROCESSING FOR CONTINUOUSANALYTE SENSORS”, which is incorporated herein by reference in itsentirety. In some embodiments, the predictive algorithms consider theamount, type, and time of medicament delivery in predicting glucosevalues. For example, a predictive algorithm that predicts a glucosevalue or trend for the upcoming 15 to 20 minutes uses a mathematicalalgorithm (for example, regression, smoothing, or the like) such asdescribed in the above-cited provisional patent application 60/528382 toproject a glucose value. However outside influences, includingmedicament delivery may cause this projection to be inaccurate.Therefore, some embodiments provide programming in the receiver thatuses the medicament delivery information received from the deliverydevice 14, in addition to other mathematical equations, to moreaccurately predict glucose values in the future.

In some alternative embodiments, the medicament delivery device 16includes one or more transdermal patches 58 suitable for administeringmedicaments as is appreciated by one skilled in the art. WO 02/43566describes one such transdermal patch, which may be used in the preferredembodiments. Although the above-cited reference and descriptionassociated with the Figs. 5A to 5C describe a medicament (for example,glucagon) useful for treating hypoglycemia, it is understood thattransdermal patches that release a medicament (for example, insulin)useful for treating hyperglycemia are also contemplated within the scopeof the preferred embodiments.

Figs. 5A to 5C are perspective views of an integrated system 10 in oneembodiment, wherein a receiver 14 is integrated with a medicamentdelivery device 16 in the form of one or more transdermal patches 58housed within a holder 56, and optionally includes a single pointglucose monitor 18, which will be described in more detail elsewhereherein. The receiver 14 receives, processes, and displays data from thecontinuous glucose monitor 12, such as described in more detail above.The medicament delivery device 16 is in the form of one or moretransdermal patches 58 held in a holder 56, which may comprise any knownpatch configuration.

The integration of the patches 58 with the receiver 14 includes similarfunctionality and provides similar advantages as described withreference to other manual integrations including manual medicamentdelivery devices (for example, syringe and inhaler). However, a uniqueadvantage may be seen in the integration of a continuous glucose sensorwith a glucagon-type patch. Namely, a continuous glucose sensor, such asdescribed in the preferred embodiments, provides more than single pointglucose readings. In fact, because the continuous glucose sensor 12knows the concentration, rate-of-change, acceleration, the amount ofinsulin administered (in some embodiments), and/or individual patternsassociated with a patient’s glucose trends (learned over time asdescribed in more detail elsewhere herein), the use of the glucagonpatch can be iteratively optimized (inputting its usage into thereceiver and monitoring the individual’s metabolic response) toproactively preempt hypoglycemic events and maintain a more controlledrange of glucose values. This may be particularly advantageous fornighttime hypoglycemia by enabling the diabetic patient (and his/hercaretakers) to improve overall nighttime diabetic health. While notwishing to be bound by theory, the integration of the continuous glucosesensor and transdermal glucagon-type patch can provide diabetic patientswith a long-term solution to reduce or avoid hypoglycemic events.

In some embodiments, the holder 58 is detachably connectable to thereceiver 14 (for example on the side opposite the LCD), which enablesconvenient availability of the patch to the patient when the receiverindicates that a medicament (for example, glucose or glucagon) isrecommended. It is further noted that although this holder is shownwithout another medicament delivery device 16 in the illustrations ofFigs. 5A to 5C, other medicaments (for example, insulin pen, insulinpump, such as described with reference to Figs. 6 and 7) may beintegrated into the system in combination with the medicament patchillustrated herein. While not wishing to be bound by theory, it isbelieved that by combining medicaments that aid the diabetic patient indifferent ways (for example, medicaments for treating hyper- andhypo-glycemic events, or, fast-acting and slow-acting medicaments), asimplified comprehensive solution for treating diabetes may be provided.

Manual Integration of delivery devices with the continuous glucosesensor 12 of the preferred embodiments may additionally be advantageousbecause the continuous device of the preferred embodiments is able totrack glucose levels long-term (for example weeks to months) andadaptively improve therapy decisions based on the patients response overtime.

In some alternative embodiments, the medicament delivery device 16includes an inhaler or spray device suitable for administering amedicament into the circulatory system, as is appreciated by one skilledin the art. Some examples of inhalers suitable for use with thepreferred embodiments include U.S. Patents 6,167,880, 6,051,551,6,024,090, which are incorporated herein by reference in their entirety.In some embodiments, the inhaler or spray device is considered a manualmedicament delivery device, such as described with reference to Figs. 4and 5, wherein the inhaler or spray is manually administered by apatient, and wherein the patient manually enters data into thecontinuous receiver about the time, amount, and types of therapy.However, it is also possible that the inhaler or spray device used foradministering the medicament may also comprise a microprocessor andoperable connection to the receiver (for example, RF), such that data issent and received between the receiver and inhaler or spray device,making it a semi-automated integration, which is described in moredetail with reference to the integrated insulin pen below, for example.

In some embodiments, the inhaler or spray device is integrally housedwithin, detachably connected to, or otherwise physically associated with(for example, in a kit) to the receiver. The functionality andadvantages for the integrated inhaler or spray device are similar tothose described with reference to the syringe and/or patch integration,above. It is noted that the inhaler or spray device may be provided incombination with any other of the medicament delivery devices of thepreferred embodiments, for example, a fast-acting insulin inhaler and aslow acting insulin pump may be advantageously integrated into thesystem of the preferred embodiments and utilized at the appropriate timeas is appreciated by one skilled in the art. In some embodiments,wherein the inhaler or spray device includes a semi-automatedintegration with the receiver, the inhaler or spray device may byphysically integrated with receiver such as described above and alsooperably connected to the receiver, for example via a wired (forexample, via electrical contacts) or wireless (for example, via RF)connection.

In one alternative embodiment, a manual medicament delivery pump isimplanted such as described in U.S. Patent 6,283,944, which isincorporated herein by reference in its entirety. In this alternativeembodiment, the patient-controlled implantable pump allows the patientto press on the device (through the skin) to administer a bolusinjection of a medicament when needed. It is believed that providingglucagon or other medicament for treating hypoglycemia within thisdevice will provide the ease and convenience that can be easily releasedby the patient and/or his or her caretaker when the continuous glucosesensor indicates severe hypoglycemia, for example. In some alternativeembodiments, the manual implantable pump is filled with insulin, orother medicament for treating hyperglycemia. In either case, the manualpump and continuous glucose sensor will benefit from manual integrationsdescribed in more detail above.

In another alternative embodiment, a cell transplantation device, suchas described in U.S. Patents 6,015,572, 5,964,745, and 6,083,523, whichare incorporated herein by reference in their entirety, is manuallyintegrated with the continuous sensor of the preferred embodiments. Inthis alternative embodiment, a patient would be implanted with betaislet cells, which provide insulin secretion responsive to glucoselevels in the body. The receiver associated with the implantable glucosesensor can be programmed with information about the cell transplantation(for example, time, amount, type, etc). In this way, the long-termcontinuous glucose sensor may be used to monitor the body’s response tothe beta islet cells. This may be particularly advantageous when apatient has been using the continuous glucose sensor for some amount oftime prior to the cell transplantation, and the change in theindividual’s metabolic patterns associated with the transplantation ofthe cells can be monitored and quantified. Because of the long-termcontinuous nature of the glucose sensor of the preferred embodiments,the long-term continuous effects of the cell transplantation can beconsistently and reliably monitored. This integration may beadvantageous to monitor any person’s response to cell transplantationbefore and/or after the implantation of the cells, which may be helpfulin providing data to justify the implantation of islet cells in thetreatment of diabetes.

It is noted that any of the manual medicament delivery devices can beprovided with an RF ID tag or other communication-type device, whichallows semi-automated integration with that manual delivery device, suchas described in more detail below.

Semi-automated Integration

Semi-automated integration of medicament delivery devices 16 in thepreferred embodiments includes any integration wherein an operableconnection between the integrated components aids the user (for example,patient or doctor) in selecting, inputting, or calculating the amount,type, or time of medicament delivery of glucose values, for example, bytransmitting data to another component and thereby reducing the amountof user input required. In the preferred embodiments, semi-automated mayalso refer to a fully automated device (for example, one that does notrequire user interaction), wherein the fully automated device requires avalidation or other user interaction, for example to validate or confirmmedicament delivery amounts. In some embodiments, the semi-automatedmedicament delivery device is an inhaler or spray device, a pen orjet-type injector, or a transdermal or implantable pump.

Figs. 6A and 6B are perspective views of an integrated system 10 in oneembodiment, wherein a receiver 14 is integrated with a medicamentdelivery device 16 in the form of a pen or jet-type injector,hereinafter referred to as a pen 60, and optionally includes a singlepoint glucose monitor 18, which will be described in more detailelsewhere herein. The receiver 14 receives, processes, and displays datafrom the continuous glucose monitor 12, such as described in more detailabove. The medicament delivery pen 60 of the preferred embodiments,includes any pen-type injector, such as is appreciated by one skilled inthe art. A few examples of medicament pens that may be used with thepreferred embodiments, include U.S. Patents 5,226,895, 4,865,591,6,192,891, and 5,536,249, all of which are incorporated herein byreference in their entirety.

Fig. 6A is a perspective view of an integrated system 10 in embodiment.The integrated system 10 is shown in an attached state, wherein thevarious elements are held by a mechanical means, as is appreciated byone skilled in the art. The components 14, 16, and 18(optional) are alsoin operable connection with each other, which may include a wired orwireless connection. In some embodiments, the components includeelectrical contacts that operably connect the components together whenin the attached state. In some embodiments, the components are operablyconnected via wireless connection (for example, RF), and wherein thecomponents may or may not be detachably connectable to each other. Fig.6B show the components in an unattached state, which may be useful whenthe patient would like to carry minimal components and/or when thecomponents are integrated via a wireless connection, for example.

Medicament delivery pen 60 includes at least a microprocessor and awired or wireless connection to the receiver 14, which are described inmore detail with reference to Fig. 8. In some embodiments, the pen 60includes programming that receives instructions sent from the receiver14 regarding type and amount of medicament to administer. In someembodiments, wherein the pen includes more than one type of medicament,the receiver provides the necessary instructions to determine which typeor types of medicament to administer, and may provide instructionsnecessary for mixing the one or more medicaments. In some embodiments,the receiver provides the glucose trend information (for example,concentration, rate-of-change, acceleration, or other user inputinformation) and pen 60 includes programming necessary to determineappropriate medicament delivery.

Subsequently, the pen 60 includes programming to send informationregarding the amount, type, and time of medicament delivery to thereceiver 14 for processing. The receiver 14 can use this informationreceived from the pen 60, in combination with the continuous glucosedata obtained from the sensor, to monitor and determine the patient’sglucose patterns to measure their response to each medicament delivery.Knowing the patient’s individual response to each type and amount ofmedicament delivery may be useful in adjusting or optimizing thepatient’s therapy. It is noted that individual metabolic profiles (forexample, insulin sensitivity) are variable from patient to patient.While not wishing to be bound by theory, it is believed that once thereceiver has learned (for example, monitored and determined) theindividual’s metabolic patterns, including glucose trends and associatedmedicament deliveries, the receiver can be programmed to adjust andoptimize the therapy recommendations for the patient’s individualphysiology to maintain their glucose levels within a desired targetrange. In alternative embodiments, the pen 60 may be manually integratedwith the receiver.

In some embodiments, the receiver includes algorithms that useparameters provided by the continuous glucose sensor, such as glucoseconcentration, rate-of-change of the glucose concentration, andacceleration of the glucose concentration to more particularly determinethe type, amount, and time of medicament administration. In fact, all ofthe functionality of the above-described manual and semi-automatedintegrated systems, including therapy recommendations, adaptiveprogramming for learning individual metabolic patterns, and predictionof glucose values, can be applied to the semi-automated integratedsystem 10, such as described herein. However, the semi- automatedintegrated sensing and delivery system additionally provides convenienceby automation (for example, data transfer through operable connection)and reduced opportunity for human error than may be experienced with themanual integration.

In some alternative embodiments, the semi-automated integration providesprogramming that requires at least one of the receiver 14, single pointglucose monitor 18, and medicament delivery device 16 to be validated orconfirmed by another of the components to provide a fail safe accuracycheck; in these embodiments, the validation includes algorithmsprogrammed into any one or more of the components. In some alternativeembodiments, the semi-automated integration provides programming thatrequires at least one of the receiver 14 and medicament delivery device16 to be validated or confirmed by an a human (for example, confirm theamount and/or type of medicament). In these embodiments, validationprovides a means by which the receiver can be used adjunctively, whenthe patient or doctor would like to have more control over the patient’stherapy decisions, for example. See Figs. 9 to 11 for processes that maybe implemented herein.

Although the above description of semi-automated medicament delivery ismostly directed to an integrated delivery pen, the same or similarintegration can be accomplished between a semi-automated inhaler orspray device, and/or a semi-automated transdermal or implantable pumpdevice. Additionally, any combination of the above semi-automatedmedicament delivery devices may be combined with other manual and/orautomated medicament delivery device within the scope of the preferredembodiments as is appreciated by one skilled in the art.

Automated Integration

Automated integration medicament delivery devices 16 in the preferredembodiments are any delivery devices wherein an operable connectionbetween the integrated components provides for full control of thesystem without required user interaction. Transdermal and implantablepumps are examples of medicament delivery devices that may be used withthe preferred embodiments of the integrated system 10 to provideautomated control of the medicament delivery device 16 and continuousglucose sensor 12. Some examples of medicament pumps that may be usedwith the preferred embodiments include, Patents U.S. 6,471,689, WO81/01794, and EP 1281351, both of which are incorporated herein byreference in their entirety.

Figs. 7A to 7C are perspective views of an integrated system in oneembodiment, wherein a sensor and delivery pump, which are implanted ortransdermally inserted into the patient, are operably connected to anintegrated receiver, and optionally include a single point glucosemonitor. Fig. 7A is a perspective view of a patient 8, in which isimplanted or transdermally inserted a sensor 12 and a pump 70. Figs. 7Band 7C are perspective views of the integrated receiver and optionalsingle point glucose monitor in attached and unattached states. The pump70 may be of any configuration known in the art, for example, such ascited above.

The receiver 14 receives, processes, and displays data associated withthe continuous glucose monitor 12, data associated with the pump 70, anddata manually entered by the patient 8. In some embodiments, thereceiver includes algorithms that use parameters provided by thecontinuous glucose sensor, such as glucose concentration, rate-of-changeof the glucose concentration, and acceleration of the glucoseconcentration to determine the type, amount, and time of medicamentadministration. In fact, all of the functionality of the above-describedmanual and semi-automated integrated systems, including therapyrecommendations, confirmation or validation of medicament delivery,adaptive programming for learning individual metabolic patterns, andprediction of glucose values, can be applied to the fully automatedintegrated system 10, such as described herein with reference to Figs.7A to 7C. However, the fully automated sensing and delivery system canrun with or without user interaction. Published Patent Application US2003/0028089 provides some systems and methods for providing control ofinsulin, which may be used with the preferred embodiments, and isincorporated herein by reference in its entirety.

In some embodiments of the automated integrated system 10, a fail-safemode is provided, wherein the system is programmed with conditionswhereby when anomalies or potentially clinically risky situations arise,for example when a reference glucose value (for example, from an SMBG)indicates a discrepancy from the continuous sensor that could cause riskto the patient if incorrect therapy is administered. Another example ofa situation that may benefit from a validation includes when a glucosevalues are showing a trend in a first direction that shows a possibilityof “turn around,” namely, the patient may be able to reverse the trendwith a particular behavior within a few minutes to an hour, for example.In such situations, the automated system may be programmed to revert toa semi-automated system requiring user validation or other userinteraction to validate the therapy in view of the situation.

It is noted that in the illustrated embodiment, only one receiver 14 isshown, which houses the electronics for both the medicament deliverypump 70 and the continuous sensor 12. Although it is possible to housethe electronics in two different receiver housings, providing oneintegrated housing 14 increases patient convenience and minimizesconfusion or errors. In some embodiments, the sensor receiverelectronics and pump electronics are separate, but integrated. In somealternative embodiments, the sensor and pump share the same electronics.

Additionally, the integrated receiver for the sensor and pump, can befurther integrated with any combination with the above-describedintegrated medicament delivery devices, including syringe, patch,inhaler, and pen, as is appreciated by one skilled in the art.

Single Point Glucose Monitor

In the illustrated embodiments (Figs. 4 to 7), the single point glucosemonitor includes a meter for measuring glucose within a biologicalsample including a sensing region that has a sensing membraneimpregnated with an enzyme, similar to the sensing membrane describedwith reference to U.S. Patents 4,994,167 and 4,757,022, which areincorporated herein in their entirety by reference. However, inalternative embodiments, the single point glucose monitor can use othermeasurement techniques such as optical, for example. It is noted thatthe meter is optional in that a separate meter can be used and theglucose data downloaded or input by a user into the receiver. Howeverthe illustrated embodiments show an integrated system that exploits theadvantages associated with integration of the single point glucosemonitor with the receiver 14 and delivery device 16.

Figs. 4 to 7 are perspective views of integrated receivers including asingle point glucose monitor. It is noted that the integrated singlepoint glucose monitor may be integral with, detachably connected to,and/or operably connected (wired or wireless) to the receiver 14 andmedicament delivery device 16. The single point glucose monitor 18integrates rapid and accurate measurement of the amount of glucose in abiological fluid and its associated processing with the calibration,validation, other processes associated with the continuous receiver 14,such as described in more detail with reference to co-pending U.S.provisional patent application, 60/523,840, entitled “INTEGRATEDRECEIVER FOR CONTINUOUS ANALYTE SENSOR,” which is incorporated herein byreference in its entirety.

In the illustrated embodiments, the single point glucose monitor 18,such as described in the above-cited co-pending provisional patentapplication, 60/523,840, includes a body 62 that houses a sensing region64, which includes a sensing membrane located within a port. A shuttlemechanism 66 may be provided that preferably feeds a single-usedisposable bioprotective film that can be placed over the sensing region64 to provide protection from contamination. The sensing region includeselectrodes, the top ends of which are in contact with an electrolytephase (not shown), which is a free-flowing fluid phase disposed betweenthe sensing membrane and the electrodes. The sensing region measuresglucose in the biological sample in a manner such as described in moredetail above, with reference the continuous glucose sensor and/or U.S.Patents 4,994,167 and 4,757,022. The similarity of the measurementtechnologies used for the continuous glucose sensor and the single pointglucose sensor provides an internal control that creates increasedreliability by nature of consistency and decreased error potential thatcan otherwise be increased due to combining dissimilar measurementtechniques. Additionally, the disclosed membrane system is known toprovide longevity, repeatability, and cost effectiveness, for example ascompared to single use strips, or the like. However, other single pointglucose monitors may be used with the preferred embodiments.

In one alternative embodiment, the single point glucose monitorcomprises an integrated lancing and measurement device such as describedin U.S. Patent 6,607,658 to Heller et al. In another alternativeembodiment, the single point glucose monitor comprises a near infrareddevice such as described in U.S. Patent 5,068,536 to Rosenthal et al. Inanother alternative embodiment, the single point glucose monitorcomprises a reflectance reading apparatus such as described in U.S.Patent 5,426,032 to Phillips et al. In another alternative embodiment,the single point glucose monitor comprises a spectroscopictransflectance device such as described in U.S. Patent 6,309,884 toCooper et al. All of the above patents and patent applications areincorporated in their entirety herein by reference.

In some embodiments, the single point glucose meter further comprises auser interface that includes a display 72 and a button 74; however, someembodiments utilize the display 48 and buttons 50 of the receiver 14rather than providing a separate user interface for the monitor 18. Insome embodiments the single point glucose monitor measured glucoseconcentration, prompts, and/or messages can be displayed on the userinterface 48 or 72 to guide the user through the calibration and samplemeasurement procedures, or the like. In addition, prompts can bedisplayed to inform the user about necessary maintenance procedures,such as "Replace Sensor" or "Replace Battery." The button 74 preferablyinitiates the operation and calibration sequences. The button can beused to refresh, calibrate, or otherwise interface with the single pointglucose monitor 18 as is appreciated by one skilled in the art.

Integrated Electronics

Fig. 8 is a block diagram that illustrates integrated system electronicsin one embodiment. One embodiment is described wherein themicroprocessor within the receiver performs much of the processing,however it is understood that all or some of the programming andprocessing described herein can be accomplished within continuousglucose sensor, receiver, single point glucose monitor, and/or deliverydevice, or any combination thereof. Similarly, displays, alarms, andother user interface functions may be incorporated into any of theindividual components of the integrated delivery device.

A quartz crystal 76 is operably connected to an RF transceiver 78 thattogether function to receive and synchronize data streams via an antenna80 (for example, transmission 40 from the RF transceiver 44 shown inFig. 3). Once received, a microprocessor 82 processes the signals, suchas described below.

The microprocessor 82 is the central control unit that provides theprocessing for the receiver, such as storing data, analyzing continuousglucose sensor data stream, analyzing single point glucose values,accuracy checking, checking clinical acceptability, calibrating sensordata, downloading data, recommending therapy instructions, calculatingmedicament delivery amount, type and time, learning individual metabolicpatterns, and controlling the user interface by providing prompts,messages, warnings and alarms, or the like. The ROM 84 is operablyconnected to the microprocessor 82 and provides semi-permanent storageof data, storing data such as receiver ID and programming to processdata streams (for example, programming for performing calibration andother algorithms described elsewhere herein). RAM 88 is used for thesystem’s cache memory and is helpful in data processing. For example,the RAM 88 stores information from the continuous glucose sensor,delivery device, and/or single point glucose monitor for later recall bythe user or a doctor; a user or doctor can transcribe the storedinformation at a later time to determine compliance with the medicalregimen or evaluation of glucose response to medication administration(for example, this can be accomplished by downloading the informationthrough the pc com port 90). In addition, the RAM 88 may also storeupdated program instructions and/or patient specific information. Figs.9 and 10 describe more detail about programming that is preferablyprocessed by the microprocessor 82. In some alternative embodiments,memory storage components comparable to ROM and RAM can be used insteadof or in addition to the preferred hardware, such as SRAM, EEPROM,dynamic RAM, non-static RAM, rewritable ROMs, flash memory, or the like.

In some embodiments, the microprocessor 82 monitors the continuousglucose sensor data stream 40 to determine a preferable time forcapturing glucose concentration values using the single point glucosemonitor electronics 116 for calibration of the continuous sensor datastream. For example, when sensor glucose data (for example, observedfrom the data stream) changes too rapidly, a single point glucosemonitor reading may not be sufficiently reliable for calibration duringunstable glucose changes in the host; in contrast, when sensor glucosedata are relatively stable (for example, relatively low rate of change),a single point glucose monitor reading can be taken for a reliablecalibration. In some additional embodiments, the microprocessor canprompt the user via the user interface to obtain a single point glucosevalue for calibration at predetermined intervals. In some additionalembodiments, the user interface can prompt the user to obtain a singlepoint glucose monitor value for calibration based upon certain events,such as meals, exercise, large excursions in glucose levels, faulty orinterrupted data readings, or the like. In some embodiments, certainacceptability parameters can be set for reference values received fromthe single point glucose monitor. For example, in one embodiment, thereceiver only accepts reference glucose data between about 40 and about400 mg/dL.

In some embodiments, the microprocessor 82 monitors the continuousglucose sensor data stream to determine a preferable time for medicamentdelivery, including type, amount, and time. In some embodiments, themicroprocessor is programmed to detect impending clinical risk and mayrequest data input, a reference glucose value from the single pointglucose monitor, or the like, in order to confirm a therapyrecommendation. In some embodiments, the microprocessor is programmed toprocess continuous glucose data and medicament therapies to adaptiveadjust to an individual’s metabolic patterns. In some embodiments, themicroprocessor is programmed to project glucose trends based on datafrom the integrated system (for example, medicament deliveryinformation, user input, or the like). In some embodiments, themicroprocessor is programmed to calibrate the continuous glucose sensorbased on the integrated single point glucose monitor. Numerous otherprogramming may be incorporated into the microprocessor, as isappreciated by one skilled in the art, as is described in cited patentsand patent applications here, and as is described with reference toflowcharts of Figs. 9 to 11.

It is noted that one advantage of integrated system of the preferredembodiments can be seen in the time stamp of the sensor glucose data,medicament delivery data, and reference glucose data. Namely, typicalimplementations of the continuous glucose sensor 12, wherein themedicament delivery 16 and/or single point glucose monitor 18 is notintegral with the receiver 14, the reference glucose data or medicamentdelivery data can be obtained at a time that is different from the timethat the data is input into the receiver 14. Thus, the user may notaccurately input the “time stamp” of the delivery or (for example, thetime or obtaining reference glucose value or administering themedicament) at the time of reference data input into the receiver.Therefore, the accuracy of the calibration of the continuous sensor,prediction of glucose values, therapy recommendations, and otherprocessing is subject to human error (for example, due toinconsistencies in entering the actual time of the single point glucosetest). In contrast, the preferred embodiments of the integrated systemadvantageously do no suffer from this potential inaccuracy when the timestamp is automatically and accurately obtained at the time of the event.Additionally, the processes of obtaining reference data andadministering the medicament may be simplified and made convenient usingthe integrated receiver because of fewer loose parts (for example,cable, test strips, etc.) and less required manual data entry.

A battery 92 is operably connected to the microprocessor 82 and providespower for the receiver. In one embodiment, the battery is a standard AAAalkaline battery, however any appropriately sized and powered batterycan be used. In some embodiments, a plurality of batteries can be usedto power the system. In some embodiments, a power port (not shown) isprovided permit recharging of rechargeable batteries. A quartz crystal94 is operably connected to the microprocessor 168 and maintains systemtime for the computer system as a whole.

A PC communication (com) port 90 may be provided to enable communicationwith systems, for example, a serial communications port, allows forcommunicating with another computer system (for example, PC, PDA,server, or the like). In one exemplary embodiment, the receiver is ableto download historical data to a physician’s PC for retrospectiveanalysis by the physician. The PC communication port 90 can also be usedto interface with other medical devices, for example pacemakers,implanted analyte sensor patches, infusion devices, telemetry devices,or the like.

A user interface 96 comprises a keyboard 98, speaker 100, vibrator 102,backlight 104, liquid crystal display (LCD) 106, and/or one or morebuttons 108. The components that comprise the user interface 96 providecontrols to interact with the user. The keyboard 98 can allow, forexample, input of user information about himself/herself, such asmealtime, exercise, insulin administration, and reference glucosevalues. The speaker 100 can provide, for example, audible signals oralerts for conditions such as present and/or predicted hyper- andhypoglycemic conditions. The vibrator 102 can provide, for example,tactile signals or alerts for reasons such as described with referenceto the speaker, above. The backlight 104 can be provided, for example,to aid the user in reading the LCD in low light conditions. The LCD 106can be provided, for example, to provide the user with visual dataoutput. In some embodiments, the LCD is a touch-activated screen. Thebuttons 108 can provide for toggle, menu selection, option selection,mode selection, and reset, for example. In some alternative embodiments,a microphone can be provided to allow for voice-activated control.

The user interface 96, which is operably connected to the microprocessor82 serves to provide data input and output for both the continuousglucose sensor, delivery mechanism, and/or for the single point glucosemonitor.

In some embodiments, prompts or messages can be displayed on the userinterface to guide the user through the initial calibration and samplemeasurement procedures for the single point glucose monitor.Additionally, prompts can be displayed to inform the user aboutnecessary maintenance procedures, such as "Replace Sensing Membrane" or"Replace Battery." Even more, the glucose concentration value measuredfrom the single point glucose monitor can be individually displayed.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as malfunction,outlier values, missed data transmissions, or the like, for thecontinuous glucose sensor. Additionally, prompts can be displayed toguide the user through calibration of the continuous glucose sensor.Even more, calibrated sensor glucose data can be displayed, which isdescribed in more detail with reference co-pending U.S. PatentApplications 10/633,367 and copending U.S. provisional patentapplication 60/528382, both of which are incorporated herein byreference in their entirety.

In some embodiments, prompts or messages about the medicament deliverydevice can be displayed on the user interface to inform or confirm tothe user type, amount, and time of medicament delivery. In someembodiments, the user interface provides historical data and analytespattern information about the medicament delivery, and the patient’smetabolic response to that delivery, which may be useful to a patient ordoctor in determining the level of effect of various medicaments.

Electronics 110 associated with the delivery device 16 (namely, thesemi-automated and automated delivery devices) are operably connected tothe microprocessor 82 and include a microprocessor 112 for processingdata associated with the delivery device 16 and include at least a wiredor wireless connection (for example, RF transceiver) 114 fortransmission of data between the microprocessor 82 of the receiver 14and the microprocessor 112 of the delivery device 16. Other electronicsassociated with any of the delivery devices cited herein, or other knowndelivery devices, may be implemented with the delivery deviceelectronics 110 described herein, as is appreciated by one skilled inthe art.

In some embodiments, the microprocessor 112 comprises programming forprocessing the delivery information in combination with the continuoussensor information. In some alternative embodiments, the microprocessor82 comprises programming for processing the delivery information incombination with the continuous sensor information. In some embodiments,both microprocessors 82 and 112 mutually processor information relatedto each component.

In some embodiments, the medicament delivery device 16 further includesa user interface (not shown), which may include a display and/orbuttons, for example. U.S. Patents 6,192,891, 5,536,249, and 6,471,689describe some examples of incorporation of a user interface into amedicament delivery device, as is appreciated by one skilled in the art.

Electronics 116 associated with the single point glucose monitor 18 areoperably connected to the microprocessor 120 and include a potentiostat118 in one embodiment that measures a current flow produced at theworking electrode when a biological sample is placed on the sensingmembrane, such as described above. The current is then converted into ananalog signal by a current to voltage converter, which can be inverted,level-shifted, and sent to an A/D converter. The microprocessor can setthe analog gain via its a control port (not shown). The A/D converter ispreferably activated at one-second intervals. The microprocessor looksat the converter output with any number of pattern recognitionalgorithms known to those skilled in the art until a glucose peak isidentified. A timer is then preferably activated for about 30 seconds atthe end of which time the difference between the first and lastelectrode current values is calculated. This difference is then dividedby the value stored in the memory during instrument calibration and isthen multiplied by the calibration glucose concentration. The glucosevalue in milligram per deciliter, millimoles per liter, or the like, isthen stored in the microprocessor, displayed on the user interface, usedto calibrate of the glucose sensor data stream, downloaded, etc.

Programming and Processing (Draw Flow Diagrams)

Fig. 9 is a flow chart that illustrates the process 130 of validatingtherapy instructions prior to medicament delivery in one embodiment. Insome embodiments, the therapy recommendations include a suggestion onthe user interface of time, amount, and type of medicament to delivery.In some embodiments, therapy instructions includes calculating a time,amount, and/or type of medicament delivery to administer, and optionallytransmitting those instructions to the delivery device. In someembodiments, therapy instructions include that portion of a closed loopsystem wherein the determination and delivery of medicament isaccomplished, as is appreciated by one skilled in the art.

Although computing and processing of data is increasingly complex andreliable, there are circumstances by which the therapy recommendationsnecessitate human intervention. Some examples include when a user isabout to alter his/her metabolic state, for example due to behavior suchas exercise, meal, pending manual medicament delivery, or the like. Insuch examples, the therapy recommendations determined by the programmingmay not have considered present or upcoming behavior, which may changethe recommended therapy. Numerous such circumstances can be contrived,suffice it to say that a validation may be advantageous in order toensure that therapy recommendations are appropriately administered.

At block 132, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (e.g., a data stream),including one or more time-spaced sensor data points, from a sensor viathe receiver, which may be in wired or wireless communication with thesensor. The sensor data point(s) may be raw or smoothed, such asdescribed in co-pending U.S. Patent Application 10/648,849, entitled“SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSORDATA STREAM,” which is incorporated herein by reference in its entirety.

At block 134, a medicament calculation module, which is a part of aprocessor module, calculates a recommended medicament therapy based onthe received sensor data. A variety of algorithms may be used tocalculate a recommended therapy as is appreciated by one skilled in theart.

At block 136, a validation module, which is a part of the processormodule, optionally validates the recommended therapy. The validation mayinclude a request from the user, or from another component of theintegrated system 10, for additional data to ensure safe and accuratemedicament recommendation or delivery. In some embodiments, thevalidation requests and/or considers additional input, such as time ofday, meals, sleep, calories, exercise, sickness, or the like. In someembodiments, the validation module is configured to request thisinformation from the user. In some embodiments, the validation module isresponsive to a user inputting such information.

In some embodiments, when the integrated system 10 is in fully automatedmode, the validation module is triggered when a potential risk isevaluated. For example, when a clinically risky discrepancy isevaluated, when the acceleration of the glucose value is changing or islow (indicative of a significant change in glucose trend), when it isnear a normal meal, exercise or sleep time, when a medicament deliveryis expected based on an individual’s dosing patterns, and/or a varietyof other such situations, wherein outside influences (meal time,exercise, regular medicament delivery, or the like) may deemconsideration in the therapy instructions. These conditions fortriggering the validation module may be pre-programmed and/or may belearned over time, for example, as the processor module monitors andpatterns an individual’s behavior patterns.

In some embodiments, when the integrated system 10 is in semi-automatedmode, the system may be programmed to request additional informationfrom the user regarding outside influences unknown to the integratedsystem prior to validation. For example, exercise, food or medicamentintake, rest, or the like may input into the receiver for incorporationinto a parameter of the programming (algorithms) that processing thetherapy recommendations.

At block 138, the receiver confirms and sends (for example, displays,transmits and/or delivers) the therapy recommendations. In manualintegrations, the receiver may simply confirm and display therecommended therapy, for example. In semi-automated integrations, thereceiver may confirm, transmit, and optionally delivery instructions tothe delivery device regarding the recommended therapy, for example. Inautomated integrations the receiver may confirm and ensure the deliveryof the recommended therapy, for example. It is noted that these examplesare not meant to be limiting and there are a variety of methods by whichthe receiver may confirm, display, transmit, and/or deliver therecommended therapy within the scope of the preferred embodiments.

Fig. 10 is a flow chart 140 that illustrates the process of providingadaptive metabolic control using an integrated system in one embodiment.In this embodiment, the integrated system is programmed to learn thepatterns of the individual’s metabolisms, including metabolic responseto medicament delivery.

At block 142, a medicament data receiving module, which may beprogrammed within the receiver 14 and/or medicament delivery device 16,receives medicament delivery data, including time, amount, and/or type.In some embodiments, the user is prompted to input medicament deliveryinformation into the user interface. In some embodiments, the medicamentdelivery device 16 sends the medicament delivery data to the medicamentdata-receiving module.

At block 144, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (e.g., a data stream),including one or more time-spaced sensor data points, from a sensor viathe receiver, which may be in wired or wireless communication with thesensor.

At block 146, the processor module, which may be programmed into thereceiver 14 and/or the delivery device 16 is programmed to monitor thesensor data from the sensor data module 142 and medicament delivery fromthe medicament delivery module 144 to determine an individual’smetabolic profile, including their response to various times, amounts,and/or types of medicaments. The processor module uses any patternrecognition-type algorithm as is appreciated by one skilled in the artto quantify the individual’s metabolic profile.

At block 148, a medicament calculation module, which is a part of aprocessor module, calculates the recommended medicament based on thesensor glucose data, medicament delivery data, and/or individual’smetabolic profile. In some embodiments, the recommended therapy isvalidated such as described with reference to Fig. 9 above. In someembodiments, the recommended therapy is manually, semi-automatically, orautomatically delivered to the patient.

At block 150, the process of monitoring and evaluation a patient’smetabolic profile is repeated with new medicament delivery data, whereinthe processor monitors the sensor data with the associated medicamentdelivery data to determine the individual’s metabolic response in orderto adaptively adjust, if necessary, to newly determined metabolicprofile or patterns. This process may be continuous throughout the lifeof the integrated system, may be initiated based on conditions met bythe continuous glucose sensor, may be triggered by a patient or doctor,or may be provided during a start-up or learning phase.

While not wishing to be bound by theory, it is believed that byadaptively adjusting the medicament delivery based on an individual’smetabolic profile, including response to medicaments, improved long-termpatient care and overall health can be achieved.

Fig. 11 is a flow chart 152 that illustrates the process of glucosesignal estimation using the integrated sensor and medicament deliverydevice in one embodiment. It is noted that glucose estimation and/orprediction are described in co-pending patent application 10/633,367 andprovisional patent application 60/528382, both of which have beenincorporated herein by reference in their entirety. However, thepreferred embodiments described herein, further incorporated additionaldata of medicament delivery in estimating or predicting glucose trends.

At block 154, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (e.g., a data stream),including one or more time-spaced sensor data points, from a sensor viathe receiver, which may be in wired or wireless communication with thesensor.

At block 156, the medicament data receiving module, which may beprogrammed within the receiver 14 and/or medicament delivery device 16,receives medicament delivery data, including time, amount, and/or type.

At block 158, the processor module evaluates medicament delivery datawith substantially time corresponding glucose sensor data to determineindividual metabolic patterns associated with medicament delivery.“Substantially time corresponding data” refers to that time periodduring which the medicament is delivered and its period of release inthe host.

At block 160, the processor module estimates glucose values responsiveto individual metabolic patterns associated with the medicamentdelivery. Namely, the individual metabolic patterns associated with themedicament delivery are incorporated into the algorithms that estimatepresent and future glucose values, which are believed to increaseaccuracy of long-term glucose estimation.

Examples

In one exemplary implementation of the preferred embodiments, thecontinuous glucose sensor (and its receiver) comprises programming totrack a patient during hypoglycemic or near-hypoglycemic conditions. Inthis implementation, the processor includes programming that sendsinstructions to administer a hypoglycemic treating medicament, such asglucagon, via an implantable pump or the like, when the glucose leveland rate of change surpass a predetermined threshold (for example, 80mg/dL and 2 mg/dL/min). In this situation, the sensor waits apredetermined amount of time (for example, 40 minutes), while monitoringthe glucose level, rate of change of glucose, and/oracceleration/deceleration of glucose in the patient, wherein if the rateof change and/or acceleration shows a changing trend away fromhypoglycemia (for example, decreased deceleration of glucose levels tonon-hypoglycemia, then the patient need not be alarmed. In this way, theautomated glucagon delivery device can proactively preempt hypoglycemicconditions without alerting or awaking the patient.

In another exemplary implementation of the preferred embodiments, acontinuous glucose sensor is integrated with a continuous medicamentdelivery device (for example, an insulin pump) and a bolus medicamentdelivery device (for example, and insulin pen). In this embodiment, theintegration takes exploits the benefits of automated and semi-automateddevice, for example, providing an automated integration with an infusionpump, while provide semi-automated integration with an insulin pen asnecessary.

In yet another exemplary implementation of the preferred embodiments, amedicament delivery device is provided that includes reservoirs of bothfast acting insulin and slow acting insulin. The medicament deliverydevice is integrated with the receiver as described elsewhere herein,however in this implementation, the receiver determines an amount offast acting insulin and an amount of slow acting insulin, wherein themedicament delivery device is configured to mix slow- and fast- actinginsulin in the amounts provided. In this way, the receiver andmedicament delivery device can work together in a feedback loop toiteratively optimize amounts of slow and fast acting insulin for avariety of situations (for example, based on glucose level, rate ofchange, acceleration, and behavioral factors such as diet, exercise,time of day, etc.) adapted to the individual patient’s metabolicprofile.

In yet another exemplary implementation of the preferred embodiments, anintegrated hypo- and hyper-glycemic treating system is provided. In thisimplementation, a manual-, semi-automated, or automated integration ofan insulin delivery device is combined with a manual-, semi-automated,or automated integration of a glucose or glucagon delivery device. Thesedevices are integrated with the receiver for the continuous glucosesensor in any manner described elsewhere herein. While not wishing to bebound by theory, it is believed that the combination of a continuousglucose sensor, integrated insulin device, and integrated glucose orglucagon device provides a simplified, comprehensive, user friendly,convenient, long-term and continuous method of monitoring, treating, andoptimizing comprehensive care for diabetes.

Methods and devices that can be suitable for use in conjunction withaspects of the preferred embodiments are disclosed in copendingapplications including U.S. Application No. 10/695,636 filed October 28,2003 and entitled, “SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE”;U.S. Patent Application No. 10/648,849 entitled, “SYSTEMS AND METHODSFOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM,” filedAugust 22, 2003; U.S. Patent Application No. 10/646,333 entitled,“OPTIMIZED SENSOR GEOMETRY FOR AN IMPLANTABLE GLUCOSE SENSOR,” filedAugust 22, 2003; U.S. Patent Application No. 10/647,065 entitled,“POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES,” filed August 22,2003; U.S. Patent Application Nos. 10/633,367, 10/632,537, 10/633,404,and 10/633,329, each entitled, “SYSTEM AND METHODS FOR PROCESSINGANALYTE SENSOR DATA,” filed August 1, 2003; U.S. Patent Application No.09/916,386 filed July 27, 2001 and entitled “MEMBRANE FOR USE WITHIMPLANTABLE DEVICES”; U.S. Patent Application No. 09/916,711 filed July27, 2001 and entitled “SENSING REGION FOR USE WITH IMPLANTABLE DEVICE”;U.S. Patent Application No. 09/447,227 filed November 22, 1999 andentitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. PatentApplication No. 10/153,356 filed May 22, 2002 and entitled “TECHNIQUESTO IMPROVE POLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSE SENSORS”; U.S.Appl. No. 09/489,588 filed January 21, 2000 and entitled “DEVICE ANDMETHOD FOR DETERMINING ANALYTE LEVELS”; U.S. Patent Application No.09/636,369 filed August 11, 2000 and entitled “SYSTEMS AND METHODS FORREMOTE MONITORING AND MODULATION OF MEDICAL DEVICES”; and U.S. PatentApplication No. 09/916,858 filed July 27, 2001 and entitled “DEVICE ANDMETHOD FOR DETERMINING ANALYTE LEVELS,” as well as issued patentsincluding U.S. 6,001,067 issued December 14, 1999 and entitled “DEVICEAND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S. 4,994,167 issuedFebruary 19, 1991 and entitled “BIOLOGICAL FLUID MEASURING DEVICE”; andU.S. 4,757,022 filed July 12, 1988 and entitled “BIOLOGICAL FLUIDMEASURING DEVICE.” All of the above patents and patent applications areincorporated in their entirety herein by reference.

The above description provides several methods and materials of theinvention. This invention is susceptible to modifications in the methodsand materials, as well as alterations in the fabrication methods andequipment. Such modifications will become apparent to those skilled inthe art from a consideration of this application or practice of theinvention provided herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments provided herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention as embodied in the attached claims.All patents, applications, and other references cited herein are herebyincorporated by reference in their entirety.

1. A method for treating diabetes with an integrated glucose sensor andmedicament delivery device, the method comprising: receiving in areceiver a data stream from a glucose sensor, including one or moresensor data points; calculating medicament therapy responsive to the oneor more sensor data points; validating the calculated therapy based onat least one of data input into said receiver and data obtained from anintegrated single point glucose monitor; and outputting validatedinformation reflective of the therapy recommendations.
 2. The methodaccording to claim 1, wherein the therapy validation is configured totrigger a fail-safe module, if the validation fails, wherein the usermust confirm a therapy decision prior to outputting therapyrecommendations.
 3. The method according to claim 1, wherein output stepincludes outputting the sensor therapy recommendations to a userinterface.
 4. The method of claim 3, wherein the wherein output stepincludes displaying the sensor therapy recommendations on the userinterface of at least one of a receiver and a medicament deliverydevice.
 5. The method according to claim 1, wherein output step includestransmitting the therapy recommendations to a medicament deliverydevice.
 6. The method according to claim 1, wherein output step includesdelivering the recommended therapy via an automated delivery device. 7.A method for treating diabetes in a host with an integrated glucosesensor and medicament delivery device, the method comprising: receivingin a receiver medicament delivery data responsive to medicament deliveryfrom a medicament delivery device; receiving in a receiver a data streamfrom a glucose sensor, including one or more sensor data points for atime period before and after the medicament delivery; determining ahost’s metabolic response to the medicament delivery; receiving asubsequent data stream from the glucose sensor including one or moresensor data points; and calculating medicament therapy responsive to thehost’s metabolic response to the medicament delivery.
 8. The methodaccording to claim 7, wherein the host’s metabolic response iscalculated using a pattern recognition algorithm.
 9. The methodaccording to claim 7, wherein the step of determining a host’s metabolicresponse to medicament delivery is repeated when additional medicamentdelivery data is received by the receiver.
 10. The method according toclaim 9, wherein the host’s metabolic response iteratively determinedfor a time period exceeding one week.
 11. A method for estimatingglucose levels from an integrated glucose sensor and medicament deliverydevice, the method comprising: receiving in a receiver a data streamfrom a glucose sensor, including one or more sensor data points;receiving in the receiver medicament delivery data responsive tomedicament delivery from a medicament delivery device; evaluatingmedicament delivery data with glucose sensor data corresponding todelivery and release times of the medicament delivery data to determineindividual metabolic patterns associated with medicament delivery; andestimating glucose values responsive to individual metabolic patternsassociated with the medicament delivery.
 12. The method according toclaim 11, wherein the individual’s metabolic patterns associated withmedicament delivery are calculated using a pattern recognitionalgorithm.
 13. The method according to claim 11, wherein the step ofdetermining the individual’s metabolic patterns to medicament deliveryis repeated when the receiver receives additional medicament deliverydata.
 14. The method according to claim 13, wherein the individual’smetabolic patterns are iteratively determined for a time periodexceeding one week.
 15. An integrated system for monitoring and treatingdiabetes, the system comprising: a glucose sensor, wherein the glucosesensor substantially continuously measures glucose in a host for aperiod exceeding one week, and outputs a data stream, including one ormore sensor data points; a receiver operably connected to the glucosesensor, wherein the receiver is configured to receive the data stream;and a medicament delivery device, wherein the delivery device is atleast one of physically and operably connected to the receiver.
 16. Theintegrated system according to claim 15, wherein the glucose sensorcomprises an implantable glucose sensor.
 17. The integrated systemaccording to claim 15, wherein the glucose sensor comprises a long-termsubcutaneously implantable glucose sensor.
 18. The integrated systemaccording to claim 15, wherein the medicament delivery device comprisesa syringe detachably connectable to the receiver.
 19. The integratedsystem according to claim 15, wherein the medicament delivery devicecomprises one or more transdermal patches detachably connectable to thereceiver.
 20. The integrated system according to claim 15, wherein themedicament delivery device comprises an inhaler or spray delivery devicedetachably connectable to the receiver.
 21. The integrated systemaccording to claim 15, wherein the medicament delivery device comprisesa pen or jet-type injector.
 22. The integrated system according to claim15, wherein the medicament delivery device comprises a transdermal pump.23. The integrated system according to claim 15, wherein the medicamentdelivery device comprises an implantable pump.
 24. The integrated systemaccording to claim 15, wherein the medicament delivery device comprisesa manual implantable pump.
 25. The integrated system according to claim15, wherein the medicament delivery device comprises a celltransplantation device.
 26. The integrated system according to claim 15,wherein the medicament delivery device is detachably connected to thereceiver.
 27. The integrated system according to claim 15, wherein themedicament delivery device is operably connected to the receiver by awireless connection.
 28. The integrated system according to claim 15,wherein the medicament delivery device is operably connected by a wiredconnection.
 29. The integrated system according to claim 15, furthercomprising a single point glucose monitor, wherein the single pointglucose monitor is at least one of physically and operably connected tothe receiver.
 30. The integrated system according to claim 29, whereinglucose sensor comprises an enzyme membrane system for electrochemicaldetection of glucose the single point glucose monitor comprises anenzyme membrane system for electrochemical detection of glucose.
 31. Theintegrated system according to claim 15, wherein the receiver comprisesa microprocessor, and wherein the microprocessor comprises programmingfor calculating and outputting medicament delivery instructions.
 32. Theintegrated system according to claim 31, wherein the microprocessorfurther comprises a validation module that validates the medicamentdelivery instructions prior to outputting the instructions.
 33. Theintegrated system according to claim 15, wherein the receiver isconfigured to receive medicament delivery data responsive to medicamentdelivery for a first time period from the medicament delivery device.34. The integrated system according to claim 33, wherein the receivercomprises a microprocessor, and wherein the microprocessor comprisesprogramming to determine a host’s metabolic response to the medicamentdelivery by evaluating the sensor data points substantiallycorresponding to delivery and release of the medicament delivery for thefirst time period.
 35. The integrated system according to claim 34,wherein the microprocessor calculates medicament therapy for a secondtime period responsive to sensor data and the host’s metabolic responseto the medicament delivery.
 36. The integrated system according to claim34, wherein the microprocessor comprises programming to estimate glucosevalues responsive to glucose sensor data and host’s metabolic response.